Thomas E. Hutson, DO, PharmD: The lenvatinib/everolimus combination is a very interesting and needed therapy option for our patients with advanced renal cell carcinoma in the refractory setting. I had the privilege of being involved with the development of that regimen from its phase I start, and I’ve had the chance to treat many patients with that combination. I’ve been very pleased with the degree of activity—of its ability to produce responses that are durable with a reasonable quality of life in the second-, third-, and fourth-line settings. The phase II trial that ultimately resulted in regulatory approval in the United States was a trial that randomized patients in the second-line setting. These patients had used a prior frontline VEGF inhibitor—mainly, sunitinib or pazopanib—and were randomized to receive everolimus, which had been recognized globally as a standard refractory agent, or to lenvatinib as a single agent or to the combination of lenvatinib and everolimus.

The trial enrolled roughly 50 patients per arm. The primary endpoint of the trial was progression-free survival. Secondary endpoints included objective response rate, tolerability, and overall survival. We were pleased to report, from the phase II results, and publish that the results showed that all 3 efficacy endpoints were met. The objective tumor response rate was much higher, the overall survival benefit was seen, and the progression-free survival was higher than we had seen in a refractory patient population. For that reason, and because of its general tolerability, the combination received regulatory approval by the FDA and has now become one of the main therapies that we choose for our patients in that second-, third-, or fourth-line space.

The next step in development for lenvatinib and everolimus is to move the regimen into the frontline setting, comparing that regimen versus a combination of lenvatinib and pembrolizumab versus sunitinib. This is being studied in a trial called the CLEAR study. I’m on the steering committee for this trial, which is accruing patients right now. In the next 1 to 2 years, we hope to have high-level data to present at one of our future meetings.

Chung-Han Lee, MD, PhD: It has been my personal experience that the combination of lenvatinib plus everolimus is a highly tolerated combination in which we see few side effects that are unexpected. Especially when we think about combination therapy, we always get worried that we’re adding 2 different medications together, where there’s some sort of interaction between those 2 medications that leads to unexpected toxicities. Because these 2 medications are very well tolerated and don’t interact from a toxicity standpoint, the toxicities that are seen are very similar to single-agent lenvatinib and single-agent everolimus.
In addition to tolerability, we also consider the regimen’s efficacy. I’ve seen promising results by using the combination. In patients who have gotten lenvatinib alone, the addition of everolimus has led to additional clinical benefit. Similarly, for patients who have gotten everolimus alone and have progressed, the addition of lenvatinib also seems to provide clinical benefit.

Transcript Edited for Clarity

Transcript:

Thomas E. Hutson, DO, PharmD: The lenvatinib/everolimus combination is a very interesting and needed therapy option for our patients with advanced renal cell carcinoma in the refractory setting. I had the privilege of being involved with the development of that regimen from its phase I start, and I’ve had the chance to treat many patients with that combination. I’ve been very pleased with the degree of activity—of its ability to produce responses that are durable with a reasonable quality of life in the second-, third-, and fourth-line settings. The phase II trial that ultimately resulted in regulatory approval in the United States was a trial that randomized patients in the second-line setting. These patients had used a prior frontline VEGF inhibitor—mainly, sunitinib or pazopanib—and were randomized to receive everolimus, which had been recognized globally as a standard refractory agent, or to lenvatinib as a single agent or to the combination of lenvatinib and everolimus.

The trial enrolled roughly 50 patients per arm. The primary endpoint of the trial was progression-free survival. Secondary endpoints included objective response rate, tolerability, and overall survival. We were pleased to report, from the phase II results, and publish that the results showed that all 3 efficacy endpoints were met. The objective tumor response rate was much higher, the overall survival benefit was seen, and the progression-free survival was higher than we had seen in a refractory patient population. For that reason, and because of its general tolerability, the combination received regulatory approval by the FDA and has now become one of the main therapies that we choose for our patients in that second-, third-, or fourth-line space.

The next step in development for lenvatinib and everolimus is to move the regimen into the frontline setting, comparing that regimen versus a combination of lenvatinib and pembrolizumab versus sunitinib. This is being studied in a trial called the CLEAR study. I’m on the steering committee for this trial, which is accruing patients right now. In the next 1 to 2 years, we hope to have high-level data to present at one of our future meetings.

Chung-Han Lee, MD, PhD: It has been my personal experience that the combination of lenvatinib plus everolimus is a highly tolerated combination in which we see few side effects that are unexpected. Especially when we think about combination therapy, we always get worried that we’re adding 2 different medications together, where there’s some sort of interaction between those 2 medications that leads to unexpected toxicities. Because these 2 medications are very well tolerated and don’t interact from a toxicity standpoint, the toxicities that are seen are very similar to single-agent lenvatinib and single-agent everolimus.
In addition to tolerability, we also consider the regimen’s efficacy. I’ve seen promising results by using the combination. In patients who have gotten lenvatinib alone, the addition of everolimus has led to additional clinical benefit. Similarly, for patients who have gotten everolimus alone and have progressed, the addition of lenvatinib also seems to provide clinical benefit.